CARDIOVASCULAR PHYSIOLOGY -MYOCARDIAL … 8 MYOCARDIAL... · 2014-12-07 · Electrophysiology of...
Transcript of CARDIOVASCULAR PHYSIOLOGY -MYOCARDIAL … 8 MYOCARDIAL... · 2014-12-07 · Electrophysiology of...
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Dr. Adelina Vlad
MD PhD
CARDIOVASCULAR PHYSIOLOGY
-MYOCARDIAL PROPERTIES-
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The Cardiovascular System
Integrates three functional
parts:
The heart, a dual pump
that circulates
a liquid, the Blood,
in two serial circuits of
Vessels: the Systemic
and the Pulmonary
Circulations
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The Cardiovascular System
Provides a steep concentration gradient
from blood to the tissues for nutrients
and in the opposite direction for waste products
The gradient can be maintained by
a rapidly circulating fluid
between regions that equilibrate with the external milieu
(lungs, guts, kidneys, skin)
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Other Functions of the CV System Transports also:
hormones, signaling molecules involvement in fast
signaling processes
immune cells, antibodies, clotting proteins roles in the
immune response/defense mechanisms
heat - dissipation from the body core to the surface
thermoregulation
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Other Functions of the CV System Secrets a number of hormones and vasoactive compounds:
Atrial natriuretic peptide (ANP), produced by the atrial fibers
– is a powerful vasodilator, and enhances renal excretion of
water and sodium as well, thereby reducing blood pressure
Factors derived from endothelium: NO (endothelial derived
relaxing factor, EDRF), endothelial derived hyperpolarizing
factor (EDHF), endothelin, prostaglandins PGE2, PGI2
(prostacyclin) etc.
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Heart Physiology
Hemodynamics
Blood Physiology
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The Heart
Bla boron circ, functii CV
Myocardium
Endocardium
Pericardium
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Myocardium Excito-conductory system
Contractile myocardium
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Myocardial Properties
EXCITABILITY/ bathmotropia
AUTOMATICITY/ chronotropia
CONDUCTIBILITY/ dromotropia
CONTRACTILITY/ inotropia
RELAXATION/ lusitropia
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Electrical Properties of the Heart
Excitability bathmotropia
Automaticity chronotropia
Conductibility dromotropia
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Excitability (Bathmotropia) Of the myocardial fiber: the ability to produce a new action
potential in response to a stimulus that has a minimum threshold
intensity
Of the whole heart: the property of the myocardium to produce a
specific answer to a threshold stimulus
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Electrophysiology of the
Myocardial Fiber Myocardial fibers have polarized membranes
There are voltage differences between the intra- and
extracellular medium
Electrical phenomenons of the cell are the consequence of the
unequal distribution of ions across membranes
due to the activity of specific membrane transport systems: ion
channels, pumps, exchangers
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Ion Channels in the Myocardium
After you activate your book, you will get
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Potassium Channels Inward rectifier potassium channels, active during the resting
phase:
Kir (K1)
responsible for maintaining the resting potential at about -90
mV;
their activation is not voltage dependent, but the
conductance decreases while the membrane depolarizes
Mediator dependent K channels (acetylcholine-, adenosine-
dependent channel, KACH, Kado), determine membrane
hyperpolarization and decreases heart rate in nodal cells
ATP-dependent K channels, KATP, are directly regulated by
adenine nucleotides: low levels of intracellular ATP stimulates
it, hyperpolarizes the membrane, protecting the heart during
ischemia
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Potassium Channels Voltage gated K channels, activate slowly during the AP and play
an important role in membrane repolarization and AP duration
Transient outward current: is activated early after
depolarization, produces the Ito current responsible for phase 1
of AP. Has a role during phase 3 as well, and can be activated
by sympathetic stimulation with the shortening of the AP
duration
Ks, slow, activated early after the depolarization with a
progressive increase that reaches the peak at the end of phase
2; is stimulated by sympathetic, producing the shortening of AP
Kr, rapid, has a rapid but partial activation at the beginning of
phase 2, and a complete activation in the end of the plateau of
the AP
Kur – ultrarapid current, present in the atrial fibers, responsible
for a shorter AP in these cells
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Repolarizing Potassium Currents
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Voltage Gated Sodium Channel Active during upstroke
Inactivated by tetrodotoxine and lidocaine
Activation
gate
Inactivation
gate
Inactive
ActiveResting state
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Calcium Channels L-type (long lasting)
voltage-gated
with an activation threshold at about -40 mV
stimulated by catecholamines and Bay K 8644
inhibited by Ach and specific blockers (nifedipine, verapamil,
diltiazem)
T-type (transient)
voltage-gated
activated at a less negative threshold (< -40 mV)
produces a low current, important for the last part of diastolic
depolarization in nodal cells
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CALCIUM CHANNEL, TYPE
Property L T
Kinetics: Long duration Transient
Voltage activation: High threshold
(>-40 mV)
Low threshold
(<-40 mV)
Pharmacology: Blocked by DHPs Less sensitive to DHPs
Location: Heart, skeletal muscle,
neurons, vascular smooth
muscle, uterus,
neuroendocrine cells
Sinoatrial node of
heart, brain neurons
Function: Phase 2 of the AP in
working fibers, upstroke of
AP in nodal cells, EC
coupling in skeletal muscle
Repetitive firing of
action potentials in
heart and many
neurons
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Nonselective Ion Channels Nonselective channel that mediate the pacemaker current, If
(the funny current), responsible for spontaneous diastolic
depolarization in pacemaker cells;
allows an influx of Na+, but also the transfer of K+ in certain
circumstances;
is activated by hyperpolarization, with a threshold below -40
mV;
changes of its conductance adjusts the heart rate;
is stimulated by catecholamines, and inhibited by Ach and
ivabradine
Stretch-activated channels, responsible for the mechano-electric
feedback (AP can be influenced by myocardial stretch)
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Ion Pumps Enzimes that pump ions against gradients with energy obtained
by cleaving ATP (ATP-ases); maintain the chemical gradient
between extra- and intracellular milieu
Na+/K+ ATP-ase
pushes 2 K+ inside and 3 Na+ outside the cell
is electogenic (creates a small outward current)
provides a chemical gradient for Na+ that feeds the
secondary active exchangers (Na+/Ca++, Na+/H+)
Is inhibited by digitalis
Ca++ ATP-ase, involved in Ca++ extrusion from the cytoplasm
Sarcolema – lower efficiency than the Na+/Ca++ exchanger
Endoplasmic reticulum – important in myocardial relaxation
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Exchangers Secondary active transport mechanisms, depend on the activity
of Na+/K+ ATP-ase
Na+/Ca++ exchanger
Is distributed mainly at the level of the T tubules
Principal mechanism for removing Ca from the cell
Is electrogenic (exchanges 1 Ca++ for 3 Na+)
Is voltage-sensitive: at membrane potentials
< - 40 mV pushes Ca outside the cell, whereas
at > - 40 mV works in the opposite direction
Na+/H+ exchanger
Protects the heart against intracellular acidosis
during myocardial ischemia
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Cardiac Action Potentials Based on the speed of the upstroke, we can
differentiate two types of action potentials in
the myocardium:
Fast action potentials – in atrial myocytes,
Purkinje fibers and ventricular myocytes;
they have 5 distinct phases
Slow action potentials – in SAN, AVN, with
only 3 phases
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Phases of Fast Action Potential
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Phases of Fast AP Phase 4: the resting phase
with a membrane voltage maintained at about – 90 mV due to
the unequal ion distribution inside and outside the cell, and
a low membrane conductance for Na + and Ca + +, and
a high conductance for K +
the resting potential approaches the equilibrium potential for
potassium, as predicted by the Nernst equation
Phase 0: the rapid upstroke, due to a sudden increase of
membrane conductance for Na +, that makes the inside of the
cell more positive than the outside, with a change in membrane
electric polarity
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Phases of Fast AP Phase 1: the early partial repolarization - the chemical and
electrostatic forces both favor the efflux of K+ through Itochannels, and an influx of Cl-
Phase 2: during the plateau phase, the net influx of Ca++ through
L-type Ca++ channels is balanced by the efflux of K+ through IK,
IKir, and Ito currents.
Phase 3: the final repolarization, when the membrane becomes
again more negative inside, due to the efflux of K+ through iK, iK1,
and ito channels
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Repolarizing Potassium Currents
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Heterogeneity of Membrane K+
Currents in the Myocardium
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Refractoriness
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Refractory Period Once a ventricular muscle cell is activated electrically, it is
refractory to additional activation
The effective refractory period (ERP) arises because the
inward currents (INa and ICa) that are responsible for activation
are largely inactivated by the membrane depolarization.
During the ERP, an additional electrical stimulus has no effect
on the action potential.
At the end of the plateau, the cell begins to repolarize as IKincreases in magnitude. ICa and INa begin to recover from
inactivation, producing the relative refractory period (RRP),
when an additional electrical stimulus can produce an action
potential, but a smaller one than usual.
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Action potential amplitude and slope of the upstroke change as
premature action potentials are initiated at different stages of the
relative refractory period of the preceding excitation in a fast -response fiber (bar = 100 msec)
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Refractoriness And the Na+ Channel
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Refractoriness provides the heart with a measure of
electrical safety because it prevents extraneous
pacemakers (which may arise pathologically) from
triggering ectopic beats.
An extrasystolic contraction would make the heart a
less efficient pump.
Refractoriness also prevents tetanus, a feature
observed in skeletal muscle. Tetanus of the heart
would mean perpetual systole, and no further
contractions
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Response to Stimulus
Cardiac muscle Skeletal muscle
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The Law of Periodic Unexcitability The heart is unexcitable during systole
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Automaticity (Chronotropia)
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Automaticity (Chronotropia) The property of the myocardium to produce spontaneous action
potentials in a rhythmic fashion
Is based on the activity of specialized myocardial cells, able to fire
AP independently of any external stimulation; these are the so
called pacemaker cells that form three pacemaking structures:
the sino-atrial node: 70 – 80 AP/min
the atrio-ventricular node: 40 - 50 AP/ min
the bundle of His and its branches and the Purkinje network: 20
- 30 AP/min
Pacemaker cells produce slow response AP; however, Purkinje
cells discharge fast AP but are able to depolarize spontaneously
at a low rate
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Slow AP Myocardial Cells Less negative maximal diastolic potential (IKir is absent)
Spontaneous diastolic depolarization (If mediated)
Slow upstroke (ICa-L dependent)
Low amplitude
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Phases of Slow Action Potential
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Phases of Slow Action Potential Phase 0: slow upstroke, due to the regenerative activation of L-type
and T-type Ca++ channels
Phase 3: membrane repolarization/ hyperpolarization, due to gradual
activation of Kr and Ks following depolarization; IK is active until the
potential becomes low enough to activate If (the pacemaker current)
Phase 4: spontaneous diastolic depolarization, due to
activation of If by membrane hyperpolarization
decrease of K currents
recovery from inactivation of Ca channels that allows a low inward
current
Thus, the sum of a decreasing outward current (IK) and two
increasing inward currents (ICa and If) produce the slow pacemaker
depolarization associated with the SA node.
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SAN Is the Primary Pacemaker of the
Heart Cardiac myocytes contract due to AP fired by the SAN and
transmitted along well established conduction pathways
SAN discharges AP at the highest rate, inhibiting the subsidiary
centers (AVN, Purkinje fibers)
AVN can become dominant when SAN node does not produce
AP or when the electrical communication between SAN and AVN
is blocked
Purkinje cells become dominant when SAN and AVN do not fire
AP or the electrical communication between the Purkinje fibers
and the superior pacemaker centers is interrupted
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Overdrive Suppression
Recovery time of the SAN
Overdrive
Overdrive Na accumulation Na/K ATP-ase is
stimulated = 3:2 hyperpolarization
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Modulation of Pacemaker Activity
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Modulation of Pacemaker Activity
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Modulation of Pacemaker Activity
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SP and PSP Innervation of the Heart
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Effects of ANS on HR
Parasympathetic stimulation Sympathetic stimulation
ICa
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Pharmacologic Modulation of HR
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Biotechnology: pacemaker engineeringCardiac stimulator
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Changes of Normal Automatism Produces cardiac arrhythmias
Can be the result of
Enhanced automaticity
Triggered activity
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Enhanced Automaticity Enhancement of normal automaticity in latent pacemaker fibers
Development of automaticity in plain atrial or ventricular cells
Can arise when the maximum diastolic potential becomes
reduced
- to -50 mV and ICa and IK may be operative
- at membrane potentials more negative than -70 mV, due to If
Pathophysiologic states: increased catecholamines, electrolyte
disturbances (e.g. hypokalemia), hypoxia or ischemia,
mechanical stretch, drugs (e.g. digitalis)
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Triggered Activity Requires the presence of an action potential
Initiated by afterdepolarizations = depolarizing oscillations in
membrane voltage induced by preceding AP
Early afterdepolarizations (EAD) – arise during phases 2 and
3 of AP
Delayed afterdepolarizations (DAD) – arise during phase 4 of
AP
When the after-depolarization reaches threshold, triggers a
sequence of pacemaker-like action potentials that generate
extrasystoles
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EAD During a prolonged AP (bradicardia, hypokalemia, drugs that block
outward K currents etc.) Ca++ channels recover from inactivation and
can lead to a spontaneous depolarization
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DAD Spontaneous release of Ca++ from SR during Ca++ overload (digitalis
intoxication, injury-related cellular depolarization, hyperkalemia etc.)
produces a transient inward current, Iti
Iti is a composite current, resulting from
- Na+/Ca++ exchange current
- non-specific cation current
that are activated by increased intracellular Ca++ concentration
When large enough, Iti can produce a spontaneous AP
DAD
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Conductibility (Dromotropia)
Is the ability to transmit the AP
generated by the pacemaker cells in
the entire myocardial territory
Follows a well established
temporal and spatial pattern, that
predetermines the pattern of
myocardial contraction
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Intracellular Conduction The speed of AP propagation along the membrane depends on
how fast the membrane gets depolarized faster propagation in
fibers with fast AP
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Intercellular Conduction
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Intercellular Conduction The heart behaves like a sincitium
Myocardial fibers communicate through gap junctions, provided
with a number of hydrophilic membrane channels, named
connexons; they allow the passage of ions and of some
metabolites with low MW
The conduction velocity and the direction of propagation of AP in
the myocardium depends on the density, the distribution and
the activity of gap junctions
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AV node – gap junctions are rare, with an unsystematic
distribution low speed of conduction, dispersion of currents
Atrial and ventricular myocytes – dense distribution of gap
junctions at the extremities, rare on the sides higher
velocity in the longitudinal direction of the fibers than in the
transversal axis = anisotropy
Purkinje fibers – very dense distribution of gap junctions, in
all parts of the membrane very high conduction velocity;
nonetheless, the communication with ventricular myocytes
occurs only longitudinally
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Transmission of the cardiac impulse through the heart, showing the time of appearance (in fractions of a second after initial appearance at the sinoatrial node) in different parts of the heart.
Conduction Through Various Types
of Myocardial Cells
SAN: < 0.05 m/sec
AVN: 0.01 - 0.1 m/sec
Internodal and interatrial
anterior pathways: 1m/sec.
His bundle, Purkinje fibers: 2
- 4m/sec
Atrial and ventricular
myocytes 0.3-0.5 m/sec
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Has three functional regions:
Atrio-nodal (AN), a transitional zone
Nodal (N) - the middle part of the AV
node
Node-hissian (NH) region, the nodal
fibers gradually merge with the bundle
of His
AP characteristics:
Long refractory periods – provides
protection against high frequency
discharges from A to V during atrial
tachyarrhythmia
Low conduction velocity
physiologic delay of about 0,1 - 0,2 s,
allows atrial systole to occur before the
beginning of ventricular contraction
Organization of the A-V Node
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SP and PSP Influences on
Dromotropia Parasympathetic stimulation
Negative dromotropic effect: ↓ inward Ca current ↓
conduction velocity through AVN
Sympathetic stimulation
Positive dromotropic effect: ↑ inward Ca current ↑
conduction velocity through AVN
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Disturbances in AP Conduction
through the Heart
Preexcitation syndrome
Reentrant arrhythmia
Blocks
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Normally, AVN is the only access pathway for the AP towards the
ventricle
When an accessory (aberrant) pathway conducts potential directly from
A to V, providing a short circuit around the delay in the AV node
preexcitation syndrome
Antegrade conduction occurs over both the accessory pathway and
the normal conducting system
The accessory pathway, being faster, depolarizes some of the V
earlier
Accessory Conduction Pathways
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Accessory conduction pathways in cases with Wolff–Parkinson–
White syndrome.
K, bundle of Kent; J, bundle of James; M, Mahaim fibres; the
hatched area represents the atrioventricular border.
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When the accessory pathway conducts in a retrograde direction
can participate in reentrant tachycardia (PSVT)
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Re-entry
A re-entrant pathway
(re-entrant excitation or
circus movement)
Is a wave of
depolarization that
travels in an endless
circle
Occurs when an
action potential loops
and results in self-
perpetuating impulse
formation
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Re – entrant Excitation
Re-entry has three requirements:
(1) a closed conduction loop,
(2) with unidirectional conduction,
provided by a region of unidirectional
block,
(3) a sufficiently slow conduction of
action potentials around the loop
(relative to the path length and the action
potential duration)
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Unidirectional block
Partial conduction block in which impulses travel in one
direction, but not in the opposite one
May arise as a result of a local depolarization or may be
due to pathologic changes in functional anatomy
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When the pathway isn’t long enough, the head of the re-entrant
impulse “bites” its own refractory tail, resulting in extinction of the
excitation
Pathway Length ≤ APD x Conduction Velocity
APD – action potential duration
SHORT PATHWAY
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The impulse can continue to travel around a closed loop, causing re-
entrant excitation if:
the pathway around the circle is long (dilated hearts)
the velocity of conduction decreases (blockage of the Purkinje
system, ischemia, hiperpotasemia etc.)
the refractory period of the muscle is shortened (short APD) (drugs,
such as epinephrine, or after repetitive electrical stimulation)
Pathway Length > APD x Conduction Velocity
APD – action potential duration
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Blocks
AV block delay of conduction between A and V
Bundle branch blocks
Right or left BBB
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Synchronization of the Left and Right
Ventricular Contraction
is important for the efficiency of the ventricular pump.
Normal synchronic
activation of the heart
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Mechanical Consequences of the Left
Bundle Branch Block
1. Initial contraction of VD
Low pressure
2. LV free wall contraction
High pressure
RV – LV activation asynchronism
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Resynchronization Therapy